A Multiscale In Silico Investigation of the Mechanics and Dynamics of Ex Vivo Coagulation

Theories describing the coagulation cascade have been around for decades and have greatly expanded in functional detail over the past several years. However, there still exists a void in the literature on the quantification of the microscale contribution of individual blood cell mechanics on the macroscale behavior of blood clots. This is due, in part, to the fact that the trans-scale relationships between blood components are not fully understood. In this work, we aim to bridge the gap between the known cell-scale phenomena of coagulation, specifically platelet and fibrin interactions, and the measurable mechanics and dynamics of whole blood clots. The developed multiscale model consists of two main components: (1) a phenomenological model of activated platelet adhesion and contraction and (2) a mechanistic model of fibrin viscoelasticity and strain-hardening extensibility. The components of the multiscale model include stand-alone discrete element method (DEM)-based cell-scale models for the primary components of blood. The unique mechanical and dynamical behaviors observed experimentally in single-platelet and single-fiber studies can be captured by this technique due to the inclusion of phenomenological force models, namely piecewise linear functions for the adhesion exhibited by activated platelets and Hill functions for the nonlinear elastic modulus of fibrin. The isolated platelet adhesion and fibrin extension models were developed and calibrated separately before they were combined to study the emergent behavior of platelet and fibrin assemblies. The platelet and fibrin compositions were varied between simulations to assess the morphological and mechanistic differences of in silico-formed aggregates. Applying the model within a dynamic framework was also used to obtain a macroscale metric of in silico aggregate behavior that is comparable to one from existing clinical whole-blood diagnostic devices like the thromboelastogram, or TEG. Specifically, we can quantify the platelet contribution to the strength of platelet and fibrin in silico aggregates. We observed a nonlinear relationship between platelet concentration and platelet contribution that corroborates experimental studies. The culmination of the modeling efforts from this dissertation is a tool that can be used and expanded to better understand the mechanistic detail of platelet and fibrin contributions during coagulation